Review of epidemiological and toxicological studies on health effects from ingestion of asbestos in drinking water.

Asbestos is a group of naturally occurring fibrous minerals that were commonly used in the construction of cement pipes for drinking water distribution systems. These pipes deteriorate and can release asbestos fibers into drinking water, raising concerns about potential risk to human health. The objective of this work was to synthesize human, animal, and in vitro evidence on potential health risks due to ingested asbestos in drinking water and evaluate the weight of evidence (WoE) of human health risk. A systematic review of epidemiological evidence was conducted, along with critical review of animal and in vitro evidence, followed by WoE evaluation that integrated human, animal, and in vitro evidence. The systematic review included 17 human studies with health outcomes mostly related to various cancer sites, with the majority focusing on the gastrointestinal system. The WoE evaluation resulted in very low levels of confidence or insufficient evidence of a health effect for cancers in 15 organ systems and for three non-cancer endpoints. While eight studies reported possible associations with stomach cancer in males, few high-quality studies were available to verify a causal relationship. Based on high-quality animal studies, an increased risk for cancer or non-cancer endpoints was not supported, aligning with findings from human studies. Overall, the currently available body of evidence is insufficient to establish a clear link between asbestos contamination in drinking water and adverse health effects. Due to the lack of both high-quality epidemiological studies and a validated kinetic model for ingested asbestos, additional research on this association is warranted.

Prevalence of epileptiform electroencephalographic abnormalities in people without a history of seizures: A systematic review and meta-analysis.

Abnormal patterns identified on electroencephalogram (EEG) are one of the primary diagnostic tests for epilepsy. However, epidemiological studies have established that both benign and epileptiform abnormalities (EAs) occur on the EEG of nonepileptic, seizure-free people as well. The reported rates of EAs in nonepileptic, seizure-free populations vary, and the true prevalence is unknown. The primary objective of this systematic review and meta-analysis was to estimate the overall prevalence of EAs in the EEG of people without a history of seizures. Secondary aims were to characterize (1) the cortical localization of focal abnormalities, (2) the proportion of findings that occurred during standard EEG stimulation protocols, and (3) the persistence and implications of abnormalities at follow-up. A comprehensive electronic search of six bibliographic databases was completed: Embase, MEDLINE, PsycInfo, Cumulative Index of Nursing and Allied Health Literature, Cochrane Central Register for Controlled Trials, and Web of Science. No search date restrictions were applied. Overall effect size was calculated using a generalized linear mixed-effects model. Fifty-three studies, totaling 73 990 individuals, met our inclusion criteria. The overall point prevalence of EAs was 1.74% (95% confidence interval [CI] = 1.13-2.67). Due to the risk of bias in the literature, especially from participant selection, we believe this to be an overestimate of the true prevalence. Prevalence of EAs was greater in children (2.45%, 95% CI = 1.41-4.21) and the elderly (5.96%, 95% CI = 1.39-22.13) compared with adults (.93%, 95% CI = .48-1.80). Reports of developing epilepsy after an EA-positive EEG were rare. The likelihood of subsequent positive findings on follow-up EEG may be as high as 50%. Our study has limitations in that males were overrepresented in the study samples, there is substantial heterogeneity among studies, and many studies provided insufficient detail about their exclusion criteria. Nonetheless, our estimates provide benchmark data for future studies examining EAs in clinical populations, particularly behavioral and psychiatric populations.

Effect of RapidShockTM Implementation on Perishock Pause in Out-of-Hospital Cardiac Arrest.

OBJECTIVES: Shorter pauses in cardiopulmonary resuscitation (CPR) are associated with better health outcomes after out-of-hospital cardiac arrest (OHCA). Our primary objective was to examine the effect of a RapidShockTM defibrillator software upgrade compared with standard defibrillator software on the length of perishock pause during care for OHCA among adults. Secondary objectives were to assess the effects of RapidShockTM on other CPR pauses. METHODS: We conducted a retrospective cohort study between September 1, 2015 and September 30, 2020. "Standard" cardiac defibrillator software in manual interpretation mode was used for CPR delivered on or before November 30, 2018, while "RapidShockTM" software (ZOLL® Medical Corporation) was used after this date. For each study group, we calculated the perishock, perianalysis, and total CPR pause; each CPR cycle was considered an independent event. We then calculated the median and interquartile range (IQR) for observed pauses with the "Standard" and "RapidShockTM" software. Percent change in median perishock pause (shockable rhythms), perianalysis pause (non-shockable rhythms), and total CPR pause were compared between CPR administered with each software using the Mann-Whitney test. RESULTS: There were 733 and 782 distinct CPR cycles administered using "Standard" and "RapidShockTM" software, respectively. A 31.8% reduction in median perishock pause was observed with "RapidShockTM" software compared with the "Standard" software (22.0 s (IQR 18.0 - 27.0 s) vs. 15.0 s (IQR 13.0 - 19.0 s); p < 0.01). The decrease in median perishock pause was driven by a reduction in the preshock phase (18 s vs. 10 s; 44.4% decrease in median pause; p < 0.01). No differences were observed in median perianalysis pause between the two groups. When combining shockable and non-shockable rhythms, we observed a reduction of 23.5% in median CPR pause (17.0 s (IQR 11.0 - 24.0 s) vs. 13s (IQR 10.0 - 17.0 s); p < 0.01). CONCLUSIONS: Overall, we observed that the use of "RapidShockTM" defibrillator software was associated with shorter CPR pauses compared with the "Standard" software. Additional studies are required to examine whether further reductions in CPR pauses may be achieved and to investigate associations between shorter CPR pauses and health outcomes.

Biomarkers for occupational manganese exposure.

Long-term inhalation exposure to manganese (Mn) metal or its inorganic compounds can result in manganism or subclinical neurofunctional deficits. Studies have described affected workers in Mn dioxide mining, Mn-containing ore crushing and milling facilities, manufacturing of dry-cell batteries, Mn steel and alloy production plants, and in welders. The objective of this study was to critically review existing evidence on the reliability of potential biomarkers of Mn exposure, specifically the relationship between inhalation exposure to Mn particulates in different occupational settings and Mn concentrations in blood and other biological fluids and tissues, with a particular focus on whole blood as a potentially useful medium for measuring internal tissue dose. We also examined available evidence on the relationship between Mn levels in blood and adverse clinical and subclinical neurotoxic outcomes. Three bibliographic databases were searched for relevant studies and identified references were screened by two independent reviewers. Of the 6338 unique references identified, 76 articles were retained for data abstraction. Findings indicate that the relationships between Mn in blood and both external Mn exposure indices and neurofunctional impairments are limited and inconsistent. Different sources of exposure to Mn compounds, heterogeneity in the methodological approaches, and inadequate reporting of essential information limited direct comparison of the reported findings. Among the Mn-exposure biomarkers considered in this review - including biomarkers in blood, plasma, serum, erythrocytes, urine, bone, toenails, fingernails, hair, saliva - biomarkers in whole blood may provide to be most useful in Mn biomonitoring and risk assessment.

Biomarkers of environmental manganese exposure.

We conducted a critical review on biomarkers of environmental manganese (Mn) exposure to answer the following questions: 1) are there reliable biomarkers of internal Mn exposure (Mn in biological matrices) associated with external metrics of Mn exposure (Mn in environmental media)? and 2) are there accurate reference values (RVs) for Mn in biological matrices? Three bibliographic databases were searched for relevant references and identified references were screened by two independent reviewers. Of the 6342 unique references identified, 86 articles were retained for data abstraction. Our analysis of currently available evidence suggests that Mn levels in blood and urine are not useful biomarkers of Mn exposure in non-occupational settings. The strength of the association between Mn in environmental media and saliva was variable. Findings regarding the utility of hair Mn as a biomarker of environmental Mn exposure are inconsistent. Measurements of Mn in teeth are technically challenging and findings on Mn in tooth components are scarce. In non-occupationally exposed individuals, bone Mn measurements using in vivo neutron activation analysis (IVNAA) are associated with large uncertainties. Findings suggest that Mn in nails may reflect Mn in environmental media and discriminate between groups of individuals exposed to different environmental Mn levels, although more research is needed. Currently, there is no strong evidence for any biological matrix as a valid biomarker of Mn exposure in non-occupational settings. Because of methodological limitations in studies aimed at derivation of RVs for Mn in biological materials, accurate RVs are scarce.

Systematic review and meta-analysis of adverse cardiovascular events associated with proton pump inhibitors used alone or in combination with antiplatelet agents.

The potential association between major adverse cardiovascular events (MACE) and concomitant treatment with proton pump inhibitors (PPIs) and clopidogrel has been debated since 2009. Recent reports, however, suggest that PPIs may increase the risk of MACE independently of clopidogrel. This review evaluates epidemiological findings relevant to the association between PPIs, taken alone or concomitantly with antiplatelets, and the risk of MACE. A systematic review and meta-analysis were conducted. Relevant studies were identified from MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials and then screened. Included studies were categorized into three groups: Group A: PPIs versus no PPIs; Group B: combined PPIs and clopidogrel versus clopidogrel alone; Group C: combined PPIs and other drugs versus other drugs. Pooled risk ratios (RRs) were calculated for each outcome of interest in each comparison group. Of the 1667 studies identified, 118 were included in the systematic review, of which 66 were included in the meta-analyses. Among Group A observational studies, RRs for MACE outcomes were statistically significant for some patient populations but not others. Pooled RRs from Group A RCTs were not statistically significant for any outcome. Pooled RRs for Group B observational studies were statistically significant for all-cause mortality and MI, but were diminished in magnitude when pooling was restricted to propensity score matched studies or post hoc analyses of RCTs. Group C studies did not demonstrate an association with MACE. Findings do not consistently support an association between MACE and PPIs when taken alone, or concomitantly with antiplatelets.

Trends in concomitant clopidogrel and proton pump inhibitor treatment among ACS inpatients, 2000-2016.

PURPOSE: The US Food and Drug Administration (FDA) issued three safety announcements between January 2009 and October 2010 warning against concomitant use of clopidogrel and proton pump inhibitors (PPIs) due to a potential drug-drug interaction that may attenuate clopidogrel's antiplatelet activity. This primary objective of this study was to examine trends in concomitant clopidogrel/PPI use among acute coronary syndrome (ACS) inpatients in the US between 2000 and 2016, in relation to the FDA safety communications. METHODS: Adult inpatients with a primary diagnosis of ACS were identified from the Cerner Health Facts® database. The standardized (age, sex, race, and census region) prevalence of clopidogrel use with PPIs was calculated yearly and quarterly. Findings were stratified by PPIs' potential to inhibit clopidogrel's activity and by age. RESULTS: A total of 204,533 inpatients were identified. In 2008, the prevalence of concomitant clopidogrel and PPI treatment was 34.9%, decreasing to 24.4 and 16.4% in 2009 and 2010, respectively, with the decline being similar across age groups. Treatment with inhibiting PPIs (omeprazole and esomeprazole) and clopidogrel has continued to decrease since 2010, with a prevalence of 0.8% in 2016. A similar reduction was not observed with clopidogrel and non-inhibiting PPIs (pantoprazole, lansoprazole, rabeprazole, and dexlansoprazole). During the FDA warning period, the combined treatment with clopidogrel and H2 receptor antagonists, an alternative to PPIs suggested by the FDA, temporarily increased from 7.8% in 2008 to 12.8 and 14.5% in 2009 and 2010, respectively. CONCLUSIONS: Findings suggest that clinical practice recommendations made by the FDA were followed. Further research is needed to determine how changes in drug labels and the availability of new drugs may have influenced the observed trends.

Diagnosis of manganism and manganese neurotoxicity: A workshop report.

With declining exposures to manganese (Mn) in occupational settings, there is a need for more sensitive exposure assessments and clinical diagnostic criteria for manganism and Mn neurotoxicity. To address this issue, a workshop was held on November 12-13, 2020, with international experts on Mn toxicity. The workshop discussions focused on the history of the diagnostic criteria for manganism, including those developed by the Institut de Recherche Robert-Sauvé en Santé et en Sécurité du Travail (IRSST) in Quebec in 2005 and criteria developed by the Chinese government in 2002 and updated in 2006; the utility of biomarkers of exposure; recent developments in magnetic resonance imaging (MRI) for assessing Mn accumulation in the brain and diagnosing manganism; and potential future applications of metabolomics. The suggestions of the participants for updating manganism diagnostic criteria included the consideration of: i) A history of previous occupational and environmental exposure to Mn; ii) relevant clinical symptoms such as dystonia; iii) MRI imaging to document Mn accumulation in the neural tissues, including the basal ganglia; and iv) criteria for the differential diagnosis of manganism and other neurological conditions. Important research gaps include the characterization of Mn exposure and other co-exposures, exploration of the roles of different brain regions with MRI, understanding the complexity of metal ion transporters involved in Mn homeostasis, and a need for information on other neurotransmitter systems and brain regions underlying the pathophysiology of manganism.

Transitional care clinics for patients discharged from hospital without a primary care provider: A systematic review.

BACKGROUND: The transition from hospital to home is a high-risk period. Timely follow-up care is essential to reducing avoidable harms such as adverse drug events, yet may be unattainable for patients who lack attachment to a primary care provider. Transitional care clinics (TCCs) have been proposed as a measure to improve health outcomes for patients discharged from hospital without an established provider. In this systematic review, we compared outcomes for unattached patients seen in TCCs after hospital discharge relative to care as usual. METHODS: We searched the following bibliographic databases for articles published on or before August 12, 2022: MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Cochrane Database of Systematic Reviews, PsycINFO, and Web of Science. Five studies were identified that examined the effects of a dedicated postdischarge clinic on emergency department (ED) visits, readmissions, and/or mortality within 90 days of discharge for patients with no attachment to a primary care provider. RESULTS: Studies were heterogeneous in design and quality; all were from urban centers within the United States. Four of the five studies reported a reduction in either the number of ED visits or readmissions in patients seen in a TCC following hospitalization. CONCLUSIONS: TCCs may be effective in reducing hospital contacts in the period following hospital discharge in patients with no established primary care provider. Further studies are required to evaluate the health benefits attributable to the implementation of TCCs across a broad range of practice contexts, as well as the cost implications of this model.

Non-Ergot Dopamine Agonists and the Risk of Heart Failure and Other Adverse Cardiovascular Reactions in Parkinson's Disease.

Reports suggest possible risks of adverse cardiovascular reactions, including heart failure, associated with non-ergot dopamine agonist (DA) use in Parkinson's disease (PD). The objectives of our review were to evaluate the risk of heart failure and other adverse cardiovascular reactions in PD patients who received a non-ergot DA compared with other anti-PD pharmacological interventions, placebo, or no intervention. Studies were identified via searches of six bibliographic databases. Randomized controlled trials (RCTs) and non-randomized studies (NRS) were eligible for study inclusion. Random-effect meta-analyses were performed to estimate adverse cardiovascular reaction risks. Quality of evidence was assessed using GRADE. In total, forty-four studies (thirty-six RCTs and eight NRS) satisfied our inclusion criteria. A single RCT found no significant difference in the risk of heart failure with ropinirole compared with bromocriptine (odds ratio (OR) 0.39, 95% confidence interval (CI) 0.07 to 2.04; low certainty). Conversely, three case-control studies reported a risk of heart failure with non-ergot DA treatment. The quality of evidence for the risk of heart failure was judged as low or very low. Findings suggest that non-ergot DA use may be associated with adverse cardiovascular outcomes, including heart failure. Studies are needed to better understand cardiovascular risks associated with PD treatment.

Myocarditis and Pericarditis Post-mRNA COVID-19 Vaccination: Insights from a Pharmacovigilance Perspective.

Concerns remain regarding the rare cardiovascular adverse events, myocarditis and pericarditis (myo/pericarditis), particularly in younger individuals following mRNA COVID-19 vaccination. Our study aimed to comprehensively assess potential safety signals related to these cardiac events following the primary and booster doses, with a specific focus on younger populations, including children as young as 6 months of age. Using the Vaccine Adverse Events Reporting System (VAERS), the United States national passive surveillance system, we conducted a retrospective pharmacovigilance study analyzing spontaneous reports of myo/pericarditis. We employed both frequentist and Bayesian methods and conducted subgroup analyses by age, sex, and vaccine dose. We observed a higher reporting rate of myo/pericarditis following the primary vaccine series, particularly in males and mainly after the second dose. However, booster doses demonstrated a lower number of reported cases, with no significant signals detected after the fourth or fifth doses. In children and young adults, we observed notable age and sex differences in the reporting of myo/pericarditis cases. Males in the 12-17 and 18-24-year-old age groups had the highest number of cases, with significant signals for both males and females after the second dose. We also identified an increased reporting for a spectrum of cardiovascular symptoms such as chest pain and dyspnea, which increased with age, and were reported more frequently than myo/pericarditis. The present study identified signals of myo/pericarditis and related cardiovascular symptoms after mRNA COVID-19 vaccination, especially among children and adolescents. These findings underline the importance for continued vaccine surveillance and the need for further studies to confirm these results and to determine their clinical implications in public health decision-making, especially for younger populations.

Risk of myocarditis and pericarditis in mRNA COVID-19-vaccinated and unvaccinated populations: a systematic review and meta-analysis.

OBJECTIVE: To summarise the available evidence on the risk of myocarditis and/or pericarditis following mRNA COVID-19 vaccination, compared with the risk among unvaccinated individuals in the absence of COVID-19 infection. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Electronic databases (Medline, Embase, Web of Science and WHO Global Literature on Coronavirus Disease), preprint repositories (medRxiv and bioRxiv), reference lists and grey literature were searched from 1 December 2020 until 31 October 2022. STUDY SELECTION: Epidemiological studies of individuals of any age who received at least one dose of an mRNA COVID-19 vaccine, reported a risk of myo/pericarditis and compared the risk of myo/pericarditis to individuals who did not receive any dose of an mRNA COVID-19 vaccine. DATA EXTRACTION AND SYNTHESIS: Two reviewers independently conducted screening and data extraction. The rate of myo/pericarditis among vaccinated and unvaccinated groups was recorded, and the rate ratios were calculated. Additionally, the total number of individuals, case ascertainment criteria, percentage of males and history of SARS-CoV-2 infection were extracted for each study. Meta-analysis was done using a random-effects model. RESULTS: Seven studies met the inclusion criteria, of which six were included in the quantitative synthesis. Our meta-analysis indicates that within 30-day follow-up period, vaccinated individuals were twice as likely to develop myo/pericarditis in the absence of SARS-CoV-2 infection compared to unvaccinated individuals, with a rate ratio of 2.05 (95% CI 1.49-2.82). CONCLUSION: Although the absolute number of observed myo/pericarditis cases remains quite low, a higher risk was detected in those who received mRNA COVID-19 vaccinations compared with unvaccinated individuals in the absence of SARS-CoV-2 infection. Given the effectiveness of mRNA COVID-19 vaccines in preventing severe illnesses, hospitalisations and deaths, future research should focus on accurately determining the rates of myo/pericarditis linked to mRNA COVID-19 vaccines, understanding the biological mechanisms behind these rare cardiac events and identifying those most at risk.

Systematic review in evidence-based risk assessment.

Systematic reviews provide a structured framework for summarizing the available evidence in a comprehensive, objective, and transparent manner. They inform evidence-based guidelines in medicine, public policy, and more recently, in environmental health and toxicology. Many regulatory agencies have extended and adapted the well-established systematic review methods, initially developed for clinical studies, for their assessment needs. The use of systematic reviews to summarize evidence from existing human, animal, and mechanistic studies can reduce reliance on animal test data in risk assessment and can help avoid unnecessary duplication of animal experiments that have already been conducted. As alternative test methods can be expected to play an increasing role in human health risk assessment in the future, systematic reviews can be particularly helpful in validating these alternatives. The field of evidence-based toxicology has undergone extensive development since its first meeting in 2007 as a result of collaborative efforts among international experts and public health agencies, particularly with respect to the use of mechanistic data and evidence integration. The continued development and wider adoption of systematic review methodology can lead to better 3R implementation. As undertaking a systematic review can be a complex and lengthy process, it is important to understand the main steps involved. Key steps, along with current best practices, are described with references to guidance from organizations with expertise in evidence synthesis. Applications of systematic reviews in clinical, observational, and experimental studies are presented. Finally, software tools available to facilitate and increase the efficiency of completing a systematic review are described.

Risk of Adverse Cardiovascular Events Following a Myocardial Infarction in Patients Receiving Combined Clopidogrel and Proton Pump Inhibitor Treatment: A Nested Case-Control Study.

BACKGROUND: The clinical implications of potential interactions between proton pump inhibitors (PPIs) and clopidogrel have been debated for over a decade. OBJECTIVE: We assessed the association between combined clopidogrel-PPI treatment and the risk of recurrent myocardial infarction (MI) and three secondary outcomes. PATIENTS AND METHODS: A nested case-control study was conducted within Cerner Corporation's Health Facts® database. A retrospective cohort of patients who experienced a first MI and started clopidogrel treatment was created. Within this cohort, patients experiencing a second MI (cases) were matched with up to five controls. Logistic regression was used to estimate adjusted odds ratios (aORs). Findings were compared with those obtained from models with three negative control exposure drugs: H2 receptor antagonists, prasugrel, and ticagrelor. RESULTS: In total, 2890 recurrent MI cases were identified within 12 months following entry into the cohort of clopidogrel users (N = 52,006). aOR for PPI use versus non-use among clopidogrel users was 1.08 [95% confidence interval (CI) 0.95-1.23]. Similar ORs were obtained for secondary endpoints. A positive association between combined use of clopidogrel/PPIs and increased risk of MI was seen in the group aged 80-89 years (aOR 1.26; 95% CI 1.05-1.51). No associations with MI were observed for (1) H2 receptor antagonist use versus non-use among clopidogrel users or (2) PPI use versus non-use among prasugrel users or among ticagrelor users. CONCLUSIONS: Overall, our findings do not support a significant adverse clinical impact of concomitant clopidogrel/PPI use by patients with MI. Nonetheless, investigation of the possible association seen in those aged 80-89 years may be warranted.

Data on systematic review and meta-analysis of epidemiologic evidence on the association between perineal use of talc powder and risk of ovarian cancer.

This paper describes data from a systematic review and meta-analysis [1] conducted to identify and evaluate published peer reviewed evidence on the association between perineal use of talc powder and risk of ovarian cancer. These data were collected from multiple electronic bibliographic databases, as well as from grey literature sources, without applying time, language or other filters. A meta-analysis was conducted to quantitatively assess the ovarian cancer risk in relation to talc use and other potential risk factors.

Critical review of the association between perineal use of talc powder and risk of ovarian cancer.

Over the past four decades, there has been increasing concern that perineal use of talc powder, a commonly used personal care product, might be associated with an increased risk of ovarian cancer. OBJECTIVES: To critically review all available human epidemiological data on the relationship between perineal use of talc powder and ovarian cancer, with consideration of other relevant experimental evidence. METHODOLOGY: We identified 30 human studies for qualitative assessment of evidence, including 27 that were retained for further quantitative analysis. RESULTS: A positive association between perineal use of talc powder and ovarian cancer was found [OR: 1.28 (95% CI: 1.20-1.37)]. A significant risk was noted in Hispanics and Whites, in women applying talc to underwear, in pre-menopausal women and in post-menopausal women receiving hormonal therapy. A negative association was noted with tubal ligation. CONCLUSION: Perineal use of talc powder is a possible cause of human ovarian cancer.

Determinants of neurological disease: Synthesis of systematic reviews.

Systematic reviews were conducted to identify risk factors associated with the onset and progression of 14 neurological conditions, prioritized as a component of the National Population Health Study of Neurological Conditions. These systematic reviews provided a basis for evaluating the weight of evidence of evidence for risk factors for the onset and progression of the 14 individual neurological conditions considered. A number of risk factors associated with an increased risk of onset for more than one condition, including exposure to pesticides (associated with an increased risk of AD, amyotrophic lateral sclerosis, brain tumours, and PD; smoking (AD, MS); and infection (MS, Tourette syndrome). Coffee and tea intake was associated with a decreased risk of onset of both dystonia and PD. Further understanding of the etiology of priority neurological conditions will be helpful in focusing future research initiatives and in the development of interventions to reduce the burden associated with neurological conditions in Canada and internationally.